Process for the production of atorvastatin calcium

ABSTRACT

In one aspect, the invention provides a process for the production of 5-(4-Fluoro-phenyl)-2-isopropyl-4-phenyl-1-(3,5,7-trihydroxy-heptyl)-1H-pyrrole-3-carboxylic acid phenylamide hemicalcium salt, stereoisomers thereof or polymorphs thereof from a (6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-acetic acid tert-butyl ester.

PRIORITY CLAIM

The present application claims the benefit under 35 U.S.C. § 371 ofInternational Application No.: PCT/IN03/00328, filed Oct. 7, 2003, theentire contents of this application are hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention relates to a novel process for the production ofatorvastatin calcium. Particularly, the present invention relates to anovel process for the production of amorphous atorvastatin calcium from(6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-aceticacid tert-butyl ester.

BACKGROUND OF THE INVENTION

Atorvastatin calcium is known by synonyms like[R-(R*,R*)]-2-(4-fluorophenyl)-σσ,6-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl-1H-pyrrole-1-heptanoic acid hemicalcium salt;(βR,δR)-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid hemicalcium salt;[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid hemicalcium salt or(βR,δR)-2-(p-Fluorophenyl)-β,δ-dihydroxy-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrole-1-heptanoicacid hemicalcium salt.

The hemicalcium salt of[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid, a synthetic HMG-CoA reductase inhibitor, isused for the treatment of hyperlipidemia and hypercholesterolemia, bothof which are risk factors for arteriosclerosis and coronary heartdisease. Open dihydroxy carboxylic acid, lactone and various salt formsof[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid have been synthesized.

U.S. Pat. No. 5,273,995, teaches that[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid has surprising inhibition of thebiosynthesis of cholesterol. The calcium salt of[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid (2:1) (Formula I)

is more suited to formulations and has been recommended as a drug.

U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837;5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,273,995; 5,280,126;5,298,627; 5,342,952; 5,385,929; 5,397,792; European Patent 409,281; andWO 89/07598 describe various processes and key intermediates forpreparing atorvastatin.

WO 97/03958 and WO 97/03959 disclose novel crystalline forms ofatorvastatin calcium designated as Form I, Form II, Form III and Form IVand methods for their preparation, providing more favorable filtrationand drying characteristics.

WO 97/03960 and U.S. Pat. No. 6,087,511 describe procedures forconverting the crystalline form of atorvastatin calcium to an amorphousform. The processes disclosed therein involve dissolving Form Iatorvastatin calcium in a non-hydroxylic solvent like tetrahydrofuran ora mixture of tetrahydrofuran and toluene.

WO 00/71116 describes a procedure for converting the crystalline Form-Iby dissolving it in a non-hydroxylic solvent like tetrahydrofuran andprecipitating amorphous atorvastatin calcium by the addition of nonpolarhydrocarbon solvents like, n-hexane, cyclohexane or n-heptane, forexample.

It is therefore one object of the present invention to provide a novelprocess for the preparation of atorvastatin calcium, unique with respectto its simplicity, cost effectiveness and scalability.

SUMMARY OF THE INVENTION

The present invention relates to a novel process for the preparation ofatorvastatin calcium.

In one aspect, the process of the present invention comprises convertinga compound of Formula II to atorvastatin calcium (Formula I).

In certain exemplary embodiments, the process comprises treating acompound of Formula II with calcium oxide.

The process of the present invention is novel, simple, inexpensive andindustrially scalable.

Advantages of the present invention include: de-protection of a boronateester, cleavage of a tert-butyl ester and formation of a calcium saltare achieved in one step, employing a single reagent; a simple procedureinvolving inexpensive CaO is used; and the calcium salt is obtaineddirectly without the need for making sodium salt or any otherintermediates, thereby reducing the necessary number of steps.

DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE INVENTION

In certain embodiments, the novel process of the present inventionrelates to the preparation of[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid hemicalcium salt.

In one aspect, the process is a simple, one-step, economic andindustrially scalable process comprising converting(6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-aceticacid tert-butyl ester to[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid hemicalcium, its stereoisomers orpolymorphic forms.

In one embodiment, the process comprises treating(6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-aceticacid tert-butyl ester with calcium oxide in a suitable solvent.

In another embodiment, a suitable solvent is selected from water, awater miscible or a water immiscible solvent.

In certain embodiments, the solvent system used may be a single solventor a mixture of two or more solvents.

In certain other embodiments, the water miscible solvent may be selectedfrom one or more among methanol, ethanol, isopropanol, acetone, THF oracetonitrile, or a combination thereof.

In another aspect, the reaction of the present invention is carried outat suitable reaction conditions required for satisfactory conversion ofthe starting material to atorvastatin calcium. In one embodiment, thestarting material is Formula II.

In yet another aspect, the reaction may be carried out at a temperaturebetween about 25 to 100° C. In one embodiment of this aspect, thereaction is carried out at a temperature between about 40 to 70° C.

The reaction may be carried out for a time period between about 1 to 24hours. In one embodiment, the reaction is carried out for a time periodbetween about 5 to 15 hours.

After satisfactory conversion, the product may be isolated with orwithout further purification.

The present invention will now be illustrated by the following examples,which are not intended to limit the effective scope of the claims.Consequently, any variations of the invention described above are not tobe regarded as departure from the spirit and scope of the invention asclaimed. The present invention has been described in terms of itsspecific embodiments and various modifications and equivalents will beapparent to those skilled in the art and are intended to be includedwithin the scope of present invention.

EXAMPLE 1

A mixture of(6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-aceticacid tert-butyl ester (5 g, 0.007 mol), water (200 ml), methanol (200ml) and calcium oxide (5.0 g, 0.09 mol) was stirred at 50-60° C. for 10hours. After filtering the reaction mixture, the resulting clearfiltrate was concentrated to about 150 ml and washed with methyltert-butyl ether (50 ml). The aqueous layer was evaporated and the solidobtained was dissolved in THF (50 ml). The solution was filtered andconcentrated to yield[R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid hemicalcium salt.

EXAMPLE 2

A mixture of(6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-aceticacid tert-butyl ester (50 g, 0.07 mol), water (2 L), THF (2 L) andcalcium oxide (50 g, 0.9 mol) was stirred at 50-60° C. for 8 hours.After filtering the reaction mixture, the resulting clear filtrate wasconcentrated to about 1.5 L and washed with methyl tert-butyl ether (500ml). The aqueous layer was evaporated and solid obtained was dissolvedin THF (500 ml). The solution was filtered and concentrated to yieldatorvastatin calcium.

EXAMPLE 3

A mixture of(6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-aceticacid tert-butyl ester (100 g, 0.14 mol), water (3.0 L), acetonitrile(3.0 L) and calcium oxide (75 g, 1.35 mol) was stirred at 50-60° C. for12 hours. After filtering the reaction mixture, the resulting clearfiltrate was concentrated to about 3.0 L and washed with methyltert-butyl ether (1.0 L). The aqueous layer was evaporated and the solidobtained was dissolved in acetonitrile (1.0 L). The solution wasfiltered and concentrated to yield[R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid hemicalcium salt.

1. A process for the preparation of a compound of Formula I:

the process comprising the step of: treating a compound of Formula II

with a source of calcium ion.
 2. The process of claim 1, wherein thesource of calcium ion is CaO or Ca(OH)₂.
 3. The process of claim 1,wherein the treating step is carried out in a solvent.
 4. The process ofclaim 3, wherein the solvent is water, a water miscible solvent or awater immiscible solvent.
 5. The process of claim 3, wherein the solventis water or a water miscible solvent.
 6. The process of claim 4, whereinthe solvent is a single solvent or a mixture of two or more solvents. 7.The process of claim 6, wherein the solvent is selected from at leastone of methanol, ethanol, isopropanol, acetone, acetonitrile or THF. 8.The process of claim 1, wherein the treating step is carried out at atemperature between about 25 to 100° C.
 9. The process of claim 8,wherein the treating step is carried out at a temperature between about40 to 70° C.
 10. The process of claim 1, wherein the treating step iscarried out for a time period between about 1 to 24 hours.
 11. Theprocess of claim 1, wherein the treating step is carried out for a timeperiod between about 1 to 10 hours.